The present invention relates to the use of melt extrusion technology in the production of bioavailable sustained-release matrix pharmaceutical formulations. Previously, melt extrusion has been used in the production of immediate release formulations.
It is known in the pharmaceutical art to prepare compositions which provide for controlled release of pharmacologically active substances contained in the compositions after oral administration to humans and animals. Such slow release compositions are used to delay absorption of a medicament until it has reached certain portions of the alimentary tract. Such sustained-release of a medicament in the alimentary tract further maintains a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional rapid release dosage forms are administered.
Different methods of preparing controlled release pharmaceutical dosage forms have been suggested. For example, direct compression techniques, wet granulation techniques, encapsulation techniques and the like have been proposed to deliver pharmaceutically active ingredients to the alimentary tract over extended periods.
Additionally, various types of sustained release formulations are known in the art, including specially coated pellets, coated tablets and capsules wherein the slow release of the active medicament is brought about through selective breakdown of the coating of the preparation or through compounding with a special matrix to affect the release of a drug. Some sustained release formulations provide for related sequential release of a single dose of an active compound at predetermined periods after administration.
It is the intent of all sustained-release preparations to provide a longer period of pharmacologic response after the administration of the drug and is ordinarily experienced after the administration of the rapid release dosage forms. Such longer periods of response provide for many inherent therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations. This is especially true in the treatment of cancer patients or other patients in need of treatment for the alleviation of moderate to severe pain, where blood levels of an opioid analgesic medicament must be maintained at a therapeutically effective level to provide pain relief. Unless conventional rapid acting drug therapy is carefully administered at frequent intervals to maintain effective steady state blood levels of the drug, peaks and valleys in the blood level of the active drug occur because of the rapid absorption, systemic excretion of the compound and through metabolic inactivation, thereby producing special problems in maintenance of analgesic efficacy.
The prior art teaching of the preparation and use of compositions providing the sustained-release of an active compound from a carrier is basically concerned with the release of the active substance into the physiological fluid of the alimentary tract. However, it is generally recognized that the mere presence of an active substance in the gastrointestinal fluids does not, by itself, insure bioavailablity.
In order to be absorbed, the active drug substance must be in solution. The time required for a given proportion of an active substance from a unit dosage form is determined as the proportion of the amount of active drug substance release from a unit dosage form over a specified time base by a test method conducted under standardized conditions. The physiological fluids of the gastrointestinal tract are the media for determining dissolution time. The present state of the art recognizes many satisfactory test procedures to measure dissolution time for pharmaceutical compositions, and these test procedures are described in official compendia world wide.
Although there are many diverse factors which influence the dissolution of drug substance from its carrier, the dissolution time determined for a pharmacologically active substance form the specific composition is relatively constant and reproducible. Among the different factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Thus, the dissolution concentration of an active drug substance is dynamically modified in its steady state as components are removed from the dissolution medium through absorption across the tissue site. Under physiological conditions, the saturation level of the dissolved materials is replenished form the dosage form reserve to maintain a relatively uniform and constant dissolution concentration in the solvent medium providing for a steady state absorption.
The transport across a tissue absorption site of the gastrointestinal tract is influenced by the Donnan osmotic equilibrium forces on both sides of the membrane since the direction of the driving force is the difference between the concentrations of active substance on either side of the membrane, i.e., the amount dissolved in the gastrointestinal fluids and the amount present in the blood. Since the blood levels are constantly being modified by dilution, circulatory changes, tissue storage, metabolic conversion and systemic excretion, the flow of active materials is directed from the gastrointestinal tract into the blood stream.
Notwithstanding the diverse factors influencing both dissolution and absorption of a drug substance, a strong correlation has been established between the in-vitro dissolution time determined for a dosage form and (in-vivo) bioavailablity. The dissolution time and the bioavailablity determined for a composition are two of the most significant fundamental characteristics for consideration when evaluating sustained-release compositions.
Metal granulations techniques have also been suggested to provide controlled release formulations. Generally, melt granulation involves mechanically working an active ingredient in particulate form with one or more suitable binders and/or pharmaceutically acceptable excipients in a mixer until one or more of the binders melts and adheres to the surface of the particulate, eventually building up granules.
U.S. Pat. No. 4,957,681 (Klimesch, et. al.) discloses a continuous process for preparing pharmaceutical mixtures having at least two components which are continuously metered. The process includes continuously metering the individual components of the pharmaceutical mixture at a rate of at least 50 g/h on electronic differential metering balances having a metering accuracy of at least xc2x15% within time intervals of less than one minute and, additionally, having screw conveyors, thereby obtaining a substantially uniformly metered mixture; and shaping the mixture. Example 1 of the ""681 patent is representative of the process. The requisite amounts of a copolymer having a K value of 30 and obtained from 60% of N-vinylpyrrolid-2-one (NVP), stearyl alcohol and theophylline are metered via three metering balances into the hopper of an extruder and extruded. The temperatures of the extruder cylinder consisting of six shots ranged form 30-60xc2x0 C. and the die is heated to 100xc2x0 C. The resultant extrudate is then pressed into tablets of the required shape. The ""681 patent does not disclose preparation of sustained release opioid pharmaceutical formulations.
N. Follonier., et al., Hot-Melt Extruded Pellets for the Sustained Release of Highly Dosed Freely Soluble Drugs, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18 (1991) described certain diltiazem hydrochloride formulations prepared using hot-melt screw-extrusion to obtain sustained-release pellets to be filled into hard gelatin capsules. The polymers used were ethylcellulose, a copolymer of ethyl acrylate and methyl methacrylate containing quaternary ammonium groups, cellulose acetate butyrate, poly(vinyl chloride-co-vinyl acetate) and a copolymer of ethylene and vinyl acetate. In order to lower the extrusion temperature, some plasticizers were used.
WO 93/07859 describes drug loaded pellets produced through melt spheronization wherein the therapeutically active agent is blended with various excipients and binders; the formulation is fed to an extruder where it is heated and extruded at a speed of about 0.05 to 10 mm/sec. at approximately 60-180xc2x0 C. The extrudate is then cut into pieces in a pelletizer and subsequently fed to a spheronizer for uniform pellet formulation.
Despite the foregoing advances and the various techniques for preparing sustained release formulations available in the pharmaceutical art, there is a need in the art for an orally administrable opioid formulation which would provide an extended duration of effect which is also easy to prepare, e.g via melt-granulation techniques.
It is therefore an object of the present invention to provide sustained-release pharmaceutical formulations suitable for oral administration and methods for preparing the same utilizing melt-extrusion techniques.
It is also an object of the present invention to provide improved methods for producing pharmaceutical extrudates containing opioid analgesics and pharmaceutical acceptable hydrophobic materials via melt extrusion techniques.
It is a further object of the present invention to provide a sustained-release melt extruded multi-particulate formulation which need not be spheronized in order to obtain a final dosage form.
It is also an object of the present invention to provide methods of treatment for human patients in need of opioid analgesic therapy using dosage forms prepared in accordance with the methods disclosed herein.
In accordance with the above objects and others which will be apparent from the further reading of the specification and of the appended claims, the present invention is related in part to the surprising discovery that sustained-release oral opioid analgesic formulations may be prepared utilizing melt extrusion techniques to provide bioavailable unit dose products which provide analgesic in a patient for, e.g., 8-24 hours.
The invention is also related in part to a new melt-extruded oral sustained-release dosage forms which comprise a pharmaceutically acceptable hydrophobic material, a retardant selected from waxes, fatty alcohols, and fatty acids, and a drug.
More particularly, one aspect of the present invention is related to a pharmaceutical extrudate including an opioid analgesic dispersed in a matrix. Preferably, the extrudate is strand or spaghetti-shaped and has diameter from about 0.1 to about 5 mm. The extrudate is divided into unit doses of the opioid analgesic for oral administration to a patient, and provides a sustained analgesic effect for 8-24 hours or more.
The matrices preferably include a hydrophobic material and a second retardant material (preferably a hydrophobic fusible carrier) which acts to further slow or control the release of the therapeutically active agent which the formulation is exposed to aqueous solution in-vitro, or exposed to gastic and/or intestinal fluids.
Preferably, the hydrophobic material is selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.
The retardant material (hydrophobic fusible carrier) is preferably selected from natural and synthetic waves, fatty acids, fatty alcohols and mixtures of the same. Examples include beeswax and carnauba wax, stearic acid, and stearyl alcohol. This list is of course not meant to be exclusive.
The extrudate may be cut into multiparticulates by any cutting means known in the art. Preferably, the multiparticulates have a length of from about 0.1 to 5 mm in length. The multiparticulates may then be divided into unit doses such that each individual unit dose includes a dose of opioid analgesic sufficient to provide analgesia to a mammal, preferably a human patient.
The unit doses of multiparticulates may then be incorporated into a solid pharmaceutical dosage formulation, e.g. via compression or shaping into tablets, by placing a requisite amount inside a gelatin capsule, or by forming the extruded product into the form of a suppository.
The pharmaceutical extrudates of the present invention may be prepared by blending the drug together with all matrix ingredients (hydrophobic material, binder and any additional (optional) excipients), feeding the resultant mixture into an extruder heated to the requisite temperature necessary to soften the mixture sufficiently to render the mixture extrudable; extruding the viscous, heated mass as a spaghetti-like strand; allowing the extrudate to congeal and harden, and then dividing the strand into desired pieces. This may be accomplished, e.g., by cutting the strands into pellets of 1.5 mm in diameter and 1.5 mm in length. Preferably, the extrudate has a diameter of from about 0.1 and 5 mm and provides sustained release of said opioid analgesic for a time period of from about 8 to about 24 hours.
Another aspect of the invention is directed to pharmaceutical dosage forms including the extrudate prepared as outlined above. The extrudate is cut into multiparticulates using any cutting means known in the art, e.g a blade. The multiparticulates are then divided into unit doses containing an effective amount of opioid analgesic to provide analgesia or pain relief in a human patient over the desired. dosing interval. The unit dose of multiparticulates may then be incorporated into tablets, e.g. via direct compression, formed into suppositories, or encapsulated by any means known in the art.
In yet a further aspect of the invention, there is provided a method of treating a patient with sustained-release formulations prepared as described above. This method includes administering a dosage form containing the novel extrudate to a patient in need of opioid analgesic therapy. For purposes of the present invention, a unit dose is understood to contain an effective amount of the therapeutically active agent to produce pain relief and/or analgesia to the patient. One skilled in the art will recognize that the dose of opioid analgesic administered to a patient will vary due to numerous factors; e.g. the specific opioid analgesic(s) being administered, the weight and tolerance of the patient, other therapeutic agents concomitantly being administered, etc.
As mentioned above, in order for a dosage form to be effective for its intended purpose, the dosage form must be bioavailable. For purposes of the present invention, the term xe2x80x9cbioavailablexe2x80x9d is defined as the total amount of a drug substance that is absorbed and available to provide the desired therapeutic effect after administration of a unit dosage form. Generally, the bioavailablity of a given dosage form is determined by comparison to a known reference drug product, as commonly determined and accepted by Governmental Regulatory Agencies, such as the United States FDA.
The term xe2x80x9cbioavailabityxe2x80x9d is defined for purposes of the present invention as the extent to which the drug (e.g., opioid analgesic) is absorbed from the unit dosage form and is available at the side of drug action.
The terms xe2x80x9csustained releasexe2x80x9d, xe2x80x9cextended durationxe2x80x9d, and xe2x80x9ccontrolled releasexe2x80x9d are defined for purposes of the present invention as the release of the drug (e.g., opioid analgesic) at such a rate that blood (e.g., plasma) levels are maintained within the therapeutic range but below toxic levels over a period of time greater than 8 hours, more preferably for about 12 to about 24 hours, or longer.
The term xe2x80x9cunit dosexe2x80x9d is defined for purposes of the present invention as the total amount of multiparticulates needed to administered a desired dose of therapeutically active agent (e.g., opioid analgesic) to a patient.
The extrudates of the present invention preferably permit release of the opioid (or salts thereof) over a sustained period of time in an aqueous medium. The term xe2x80x9caqueous mediumxe2x80x9d is defined for purposes of the present invention as any water-containing medium, e.g. water, pharmaceutically acceptable dissolution medium, gastric fluid and/or intestinal fluid and the like.